The insulin-like growth factors (IGFs) are 7.5kD peptides, structurally homologous to insulin, which mediate many of the anabolic effects of growth hormone in vivo, and are mitogenic for a variety of cell types in vitro. Importantly, plasma and other biological fluids contain multiple proteins that specifically bind IGFs. These IGF binding proteins have distinct molecular sizes, biochemical characteristics, and immunological determinants, and may be pivotal in directing and modulating IGF action at the cellular level Three IGF binding proteins have been cloned and sequenced, but others have been detected and have yet to be characterized. The precise interactions among the various IGF binding proteins and IGF peptides, and the regulatory mechanisms for IGF binding protein production are largely unknown. Our central hypothesis is that the IGF binding proteins are integral components of IGF physiology that define and coordinate IGF and insulin action at the level of the target cell We propose that the production of IGF binding proteins in their multiple discrete forms are under specific hormonal control, and that the different IGF binding proteins have distinct biological functions in modulating IGF action. A unique feature of this proposal is the planned, stepwise integration of mechanistic experiments using both in vitro and clinical models. The specific aims of this research project are (1) to develop and carefully characterize in vitro models appropriate for the study of IGF binding proteins, (2) to determine the transcriptional and translational control of IGF binding protein synthesis under defined conditions, and assess qualitative and quantitative changes in IGF binding protein production peculiar to cell type and during development, aging, and transformation, (3) to ascertain the mechanism of action of purified IGF binding proteins, and (4) to define the regulation of IGF binding proteins in vivo since the physiological actions of IGFs are, in part, regulated by the availability and type of binding protein to which the peptide is bound. The principal investigator has expertise in the various techniques of biochemistry, molecular biology, and cellular physiology necessary for the success of this proposal. These studies will help clarify the integrated role of IGFs and IGF binding proteins in the control of cell growth, and provide important insight into the biological consequences of altered IGF binding protein production and, therefore, IGF action in various physiological and pathophysiological states.